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. 2012 May;41(5):449-60.
doi: 10.1007/s00249-012-0798-4. Epub 2012 Apr 7.

Ionizable side chains at catalytic active sites of enzymes

David Jimenez-Morales  1 , Jie Liang, Bob Eisenberg
Affiliations

Ionizable side chains at catalytic active sites of enzymes

David Jimenez-Morales et al. Eur Biophys J. 2012 May.

Abstract

Catalytic active sites of enzymes of known structure can be well defined by a modern program of computational geometry. The CASTp program was used to define and measure the volume of the catalytic active sites of 573 enzymes in the Catalytic Site Atlas database. The active sites are identified as catalytic because the amino acids they contain are known to participate in the chemical reaction catalyzed by the enzyme. Acid and base side chains are reliable markers of catalytic active sites. The catalytic active sites have 4 acid and 5 base side chains, in an average volume of 1,072 Å(3). The number density of acid side chains is 8.3 M (in chemical units); the number density of basic side chains is 10.6 M. The catalytic active site of these enzymes is an unusual electrostatic and steric environment in which side chains and reactants are crowded together in a mixture more like an ionic liquid than an ideal infinitely dilute solution. The electrostatics and crowding of reactants and side chains seems likely to be important for catalytic function. In three types of analogous ion channels, simulation of crowded charges accounts for the main properties of selectivity measured in a wide range of solutions and concentrations. It seems wise to use mathematics designed to study interacting complex fluids when making models of the catalytic active sites of enzymes.

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Figures

Figure 1
Figure 1
Sketch of the structural elements calculated and measured in this paper. (A) Catalytic active site (left hand panel). The catalytic active site in this example is in a pocket accessible from outside. Most (93%) of the actives sites in our dataset are accessible. (B) Molecular surface that defines the catalytic active site volume (unit A3). The volume is reported for both pockets and voids, but not for depressions, where it is difficult to define precisely.
Figure 2
Figure 2
Histogram of the distribution of the volume of the active site pocket for a set of 759 enzyme structures (unit: Å3) Pockets with volumes between 100 and 3,000 Å3 were used in the determination of the number of acid and base side chains and the calculation of the density of charge.
Figure 3
Figure 3
Amino acid composition in our dataset for the entire protein, all the amino acids in the active site pocket and only the catalytic amino acids. The distribution of amino acids in the entire protein and the catalytic active site are not very different. There is a significant increase of polar charged and uncharged side chains for catalytic residues.
Figure 4
Figure 4
Amino acid composition grouped by enzymes (EC1 to EC6). All the amino acids in the entire protein, in the catalytic active site pockets and only the catalytic amino acids.
Figure 5
Figure 5
Density estimation of the fraction of proteins with a given charge density (CharDen). Catalytic active site, craters and the entire protein CharDen.
Figure 6
Figure 6
Density estimation of the volume (A3) of catalytic active sites and craters
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